The long-term goal of this proposal is to test hypothesized functions of the plasminogen system in defined physiological and pathological processes utilizing gene knock-out mice and to identify previously unrecognized functions of this system. The contribution of the plasminogen system in hemostasis, through plasmin's ability to directly degrade fibrin, has been extensively analyzed and is well accepted. The identification of receptors for components of the plasminogen system on a number of cell surfaces implicates plasmin in playing a role in cell migratory events such as the inflammatory response. Paramount to this response and other cell migratory events is the degradation of extracellular matrix. Plasmin is believed to play a major role in this process either directly or through activation of other matrix degrading proteins, i.e., metalloproteases. The inflammatory response is associated with the early stages of a number of pathologies, such as pulmonary fibrosis and atheroscelerosis and regulation of these early events may dictate the clinical outcome of these diseases. The availability of gene knock-out mice to all components of the plasminogen system offers an unique opportunity to analyze, in vivo, in a mechanistic fashion its function in these pathologies. In this study mice deficient for components of the plasminogen system will be challenged utilizing two models of inflammatory diseases, pulmonary fibrosis and atherosclerosis. The effect components of the plasminogen system has on events associated with both early inflammatory response and later stages of these diseases will be investigated. Utilizing these gene knock-out mice, this proposal will specifically: (1) study bleomycin induced pulmonary fibrosis by assessing early inflammatory events; alterations in the integrity of the capillary/alveolar wall integrity; lesion development; and metalloprotease involvement. (2) study copper cuff induced atherosclerosis by determine qualitative and quantitative changes in the vessel wall and lumen utilizing a battery of histological and immunohistological techniques.